Hyperthermia as a treatment of tumors has been carefully studied and applied since the 1960's. Prior to that period there were multiple reports of tumor regression coincident with episodes of fever. Biochemical analysis of the effects of hyperthermia has indicated that temperatures greater than 41.degree. C. generally are needed to induce tumor necrosis (tumor death). Although there are multiple methods of inducing hyperthermia including paraffin wax baths, a heat chamber and a water blanket, many physicians now favor an extracorporeal heat exchange (blood) circuit when whole body heating is the goal. Patients may be maintained at 41.5.degree. to 42.degree. C. (rectal temperature) for three to four hours without severe compromise of cardiovascular function, although others report elevation of serum transaminases and bilirubin in patients kept at these temperatures for greater than 10 to 40 minutes. Instances of neurologic damage have been reported in association with serum hypophosphatemia, although no significant problems occurred once phosphate levels were maintained. Deaths have also been reported in two patients receiving hyperthermia at 41.5.degree. to 42.degree. C. for 11/2 to 2 hours, presumably from massive tumor necrosis, particularly in the liver.
DeMoss, J. L. et al., "Hyperthermia in the Treatment of Cancer," The Journal of Extra-Corporeal Technology, Volume 17, No. 1, pp. 37-43, 1985, explains how tumors are vulnerable to heat and that the goal of hyperthermic treatment therapy is to achieve cytotoxic temperatures in the tumor for a sufficient length of time without damaging the surrounding normal tissue. The rate at which blood flows through any given area of tissue determines the amount of heat that may be carried away and therefore is a major determinant of the temperature rise in that tissue. In normal tissue, heat causes vasodilation. In a tumor, the microvasculature is made up of an overabundance of capillary beds which are unable to dilate. Blood flow through the area is thus more sluggish and commensurately unable to dissipate heat applied to the area. The inability to respond to heat by dilation, as normal vasculature would, also subjects the tumor to hypoxia, anaerobic metabolism and local acidosis; these conditions in turn make the tumor tissue more vulnerable to thermal injury.
Other literature addressing the utility of hyperthermia in the treatment of malignancy includes: Sanchez, R., et al., "Overview of Whole Body Hyperthermia Experience at American International Hospital," Consensus on Hyperthermia for the 1990s, Plenum Press, New York, pp. 203-208 (1990); Levin, R. D. et al., "Whole Body Hyperthermia Experience in Breast Cancer at American International Hospital," Consensus on Hyperthermia for the 1990s, Plenum Press, New York, pp. 387-391 (1990); Perez, C. A. et al., "Randomized Phase III Study Comparing Irradiation and Hyperthermia with Irradiation Alone in Superficial Measurable Tumors," Am. J. Clin. Oncol., vol. 14, no. 2, pp. 133-141 (1991); and others.
Patents relating to methods for the extracorporeal treatment of blood for cancers, viruses and parasites include U.S. Pat. Nos. 2,886,771 to Vincent, No. 3,482,575 to Claff, 4,061,141 to Hyden et al., 4,191,182 to Popovich et al., 4,321,918 to Clark II, 4,322,275 to Jain, 4,381,004 to Babb, 4,479,798 to Parks, 4,540,401 to Marten, 4,563,170 to Aigner, 4,576,143 to Clark III and 4,692,138 to Troutner et al.
There were two reasons for exploring the use of hyperthermia as a treatment for viral-associated neoplasms when such work began a few years ago. First, hyperthermia was known to have caused tumor regression in both animal and in human sarcomas. Studies on the biochemical and physiologic effects of hyperthermia had shown that damage to microvasculature is important for tissue necrosis associated with heat. Second, the human lymphadenopathy associated virus was known to be heat-sensitive. McDougal et al. incubated lymphadenopathy associated virus at temperatures ranging from 37.degree. to 60.degree. C. and found the log kill followed first order kinetics. Thermal inactivation was decreased when the virus was in the lyophilized state compared to the liquid state (10 fold loss in LD50 121 seconds at 56.degree. C. for virus in media versus 32 minutes in lyophilized state). It was also found that lymphadenopathy virus was 40% inactivated after 30 minutes in a 42.degree. C. waterbath, and 100% inactivated after the same time period at 56.degree. C. Thus, hyperthermia can benefit patients suffering from viral infections in two ways. First, the hyperthermia kills malignant cells in the viral-associated neoplasms. Second, the hyperthermia directly inactivates the viruses themselves by denaturing them.
Studies have previously been completed in which whole body hyperthermia, achieved via extracorporeal circulation and thermoregulation, was used to treat Kaposi's Sarcoma associated with human immunodeficiency virus infection. While evaluation of the therapeutic effects of such treatment was the primary purpose of these studies, the simultaneous effects on HIV disease were evaluated by studying immunologic and virologic parameters of HIV infection as well as immunologic parameters related to Kaposi's Sarcoma.
In fact, the use of hyperthermia in acquired immunodeficiency syndrome patients with Kaposi's Sarcoma has received considerable public and media attention. The first two patients upon whom this procedure was performed were patients of the Atlanta pathologist Dr. Kenneth Alonso. Dr. Alonso initiated this experimental use of hyperthermia with Dr. William Logan, Jr., an Atlanta surgeon, as a pilot project to examine the possible use of this technique in the treatment of human immunodeficiency virus-associated diseases. Subsequently, Dr. Alonso requested that the National Institute of Allergy and Infectious Diseases (NIAID) evaluate the study techniques, results and patients.
As reported in O'Malley, S., "Hyperthermia: Perfusion's Answer . . . ?", Perfusion Life, January 1991, pp. 6-13, a patient named Carl Crawford experienced a dramatic recovery from head-to-toe skin cancers after being treated with extracorporeal blood heating. (This case study was published in Logan, W. D. et al., "Case Report: Total Body Hyperthermia in the Treatment of Kaposi's Sarcoma . . . ," Med. Oncol. & Tumor Pharmacother., vol. 8, no. 1, pp. 45-47 (1991).) Mr. Crawford had been diagnosed as having Kaposi's Sarcoma incident to human immunodeficiency virus infection, and had been told he had only two to four weeks left to live. Mr. Crawford was the first patient of Drs. Alonso and Logan, who together with perfusionist Joseph A. Guzman heated his blood to 42.degree. C. which, the doctors said, killed the human immunodeficiency virus. Although NIAID discounted Mr. Crawford's recovery due to an alleged error in diagnosis--NIAID maintained that Mr. Crawford never had Kaposi's Sarcoma but had cat-scratch fever instead-- six other doctors besides Drs. Alonso and Logan had diagnosed Mr. Crawford's skin lesions as Kaposi's Sarcoma and growing numbers of physicians are convinced that hyperthermia provides a proven antiviral protocol. For example, Dr. Robert S. Jenkins, Medical Director of the Immuno Suppressed Unit at Hollywood Community Hospital, believes that the hyperthermia was responsible for curing Mr. Crawford's Kaposi's Sarcoma lesions.
In a completely separate effort from Drs. Alonso and Logan, Dr. Shawn Hankins, a chiropractor in Port Angeles, Wash., has supported hyperthermia treatments since July, 1987 (as explained in the Acquired Immunodeficiency Syndrome Treatment News, Issue No. 104, Jun. 1, 1990, page 2). He points out that human immunodeficiency virus is heat sensitive and, in addition, hyperthermia can cause increased T-cell proliferation, phagocytosis, and increased production of antibodies and interferon. Observations of phenomenon such as the "honeymoon effect" that sometimes follows pneumocystitis (which causes a high fever) also support this conclusion.
Other publications directed generally toward the treating of human immunodeficiency virus with heat include: Weatherburn, H., "Hyperthermia . . . ," The British Journal of Radiology, vol. 61, no. 729, pp. 863-864 (1988); Yatvin, M. B., "An Approach . . . Using Hyperthermia and Membrane Modification," Medical Hypotheses, vol. 27, pp. 163-165 (1988); and U.S. Pat. No. 4,950,225 to Davidner et al., "Method for Extracorporeal Blood Shear Treatment."
The latter, Davidner et al., discusses the extracorporeal treatment of the blood of a human immunodeficiency virus patient with a) hyperthermia; b) mechanical shear and/or c) irradiation. When hyperthermia is used, the blood is heated to between 41.0.degree. and 42.5.degree. C. (or somewhat higher), and pH is adjusted by oxygenating the blood with an extracorporeal oxygenator and by adding sodium bicarbonate intravenously when necessary. Blood is held under low flow or static conditions, extracorporeally, so that the blood treatment or treatments are (assertedly) maximally successful in ineffectuating the human immunodeficiency virus.
Among the known protocols for heating blood, various difficulties persist, including (as outlined above) elevated serum transaminases and bilirubin, instances of neurologic damage associated with serum hypophosphatemia, risk due to abnormal pH or to abnormal sodium, sodium bicarbonate or potassium levels, and possible death from massive tumor necrosis. Previously attempted treatments of human immunodeficiency virus with hyperthermia have included some measures to maintain normal blood physiology (the sodium bicarbonate addition of Davidner et al., for example) in what can best be characterized as a "shotgun" approach to minimizing hyperthermia side effects. A need therefore remains for a more reliable, simpler and more comprehensive extracorporeal hyperthermia treatment method in which unwanted side effects are reduced or eliminated altogether.